Chronic inhalation of
2-butoxyethanol resulted in an increase in liver
hemangiosarcomas and hepatic
carcinomas in male mouse liver. No increase in liver
neoplasia was observed in similarly exposed male and female rats or female mice. We proposed that the production of liver
neoplasia in the male mouse is the result of oxidative damage secondary to the hemolytic deposition of
iron in the liver. This occurs selectively in the male mouse and leads either directly or indirectly to liver
neoplasia. To address this proposal, male B6C3F1 mice and male F344 rats were treated with
2-butoxyethanol (via daily gavage; five times per week) at doses of 0, 225, 450, and 900 mg/kg/day (mice) and 0, 225, and 450 mg/kg/day (rats) respectively. Following treatment for 7, 14, 28, and 90 days,
DNA synthesis, oxidative damage, hematocrit, and
iron deposition were measured in the livers. An increase in
hemolysis (measured by a decrease in hematocrit and increase in relative spleen weight) was observed in 2-butoxyethanol-treated rats and mice in a dose-dependent manner. An increase in the percentage of
iron-stained Kupffer cells was observed following treatment with 450 and 900 mg/kg of
2-butoxyethanol in mice and 225 and 450 mg/kg of
2-butoxyethanol in rats. A biphasic increase in oxidative damage (
8-hydroxydeoxyguanosine and
malondialdehyde) was seen in mouse liver after 7 and 90 days of treatment with
2-butoxyethanol, whereas no increases were observed in treated rat liver.
Vitamin E levels were reduced by
2-butoxyethanol treatment in both mice and rat liver; however, the basal level of
vitamin E was approximately 2.5-fold higher in rat than in mouse liver. A similar biphasic induction of
DNA synthesis was seen following
2-butoxyethanol treatment in the mouse. In the mouse liver, increased
DNA synthesis was observed in hepatocytes at 90 days and in endothelial cells at 7 and 14 days at all doses. No change in
DNA synthesis was seen in 2-butoxyethanol-treated rat liver. No apparent differences in apoptosis and mitosis in the liver were observed in mouse and rat liver between
2-butoxyethanol treatment groups and untreated controls. These results suggest that
DNA synthesis, possibly from oxidative stress or Kupffer cell activation, occurs selectively in the mouse liver, primarily in endothelial cells (a target of 2-butoxyethanol
neoplasia), following exposure to
2-butoxyethanol.